sanofi pasteur 14 July 2010 v /371 Fluzone 372 Fluzone High-Dose LE

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use (Influenza Virus Vaccine) or High-Dose (Influenza Virus Vaccine) safely and effectively. See full prescribing information for and High-Dose. (Influenza Virus Vaccine) High-Dose (Influenza Virus Vaccine) Suspension for Intramuscular Injection Formula Initial US Approval (): RECENT MAJOR CHANGES Indications and Usage (1) [12/2009] Dosage and Administration (2) [12/2009] Warnings and Precautions (5) [07/2010] INDICATIONS AND USAGE is an inactivated influenza virus vaccine indicated for active immunization of persons 6 months of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. (1) High-Dose is an inactivated influenza virus vaccine indicated for active immunization of persons 65 years of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. (1) This indication is based on the immune response elicited by High-Dose; there have been no controlled clinical studies demonstrating a decrease in influenza disease after vaccination with High-Dose DOSAGE AND ADMINISTRATION Vaccination Status and Age Dose/Route Schedule Previously unvaccinated or incompletely vaccinated with an influenza vaccine (ie, no previous dose or vaccinated for the first time in the last influenza season and received only 1 dose) 6 through 35 months 0.25 ml/intramuscular 2 doses at least 1 month apart 36 months through 8 years 0.5 ml/intramuscular 2 doses at least 1 month apart Previously vaccinated with an influenza vaccine (ie, received two doses last influenza season or one or more doses at any time before last season) 6 through 35 months 0.25 ml/intramuscular 1 dose 36 months through 8 years 0.5 ml/intramuscular 1 dose Any vaccination status 9 years and older 0.5 ml/intramuscular 1 dose High-Dose - Adults 65 years of age and older Any vaccination status Dose/Route Schedule 65 years and older 0.5 ml/intramuscular 1 dose DOSAGE FORMS AND STRENGTHS Sterile suspension for intramuscular injection supplied in four presentations: Prefilled syringe, 0.25 ml, pediatric dose, distinguished by a pink syringe plunger rod (3) Prefilled syringe, 0.5 ml, distinguished by a clear syringe plunger rod (3) Single-dose vial, 0.5 ml (3) Multi-dose vial, 5 ml, for 6 months of age and older, contains thimerosal as a preservative. (3, 11) Each 0.25 ml dose is formulated to contain a total of 22.5 mcg (7.5 mcg of each strain) of influenza virus hemagglutinin and each 0.5 ml dose is formulated to contain a total of 45 mcg (15 mcg of each strain) of influenza virus hemagglutinin. (3, 11) High-Dose Sterile suspension for intramuscular injection supplied in prefilled syringes, 0.5 ml, distinguished by a gray syringe plunger rod. (3) Each 0.5 ml dose is formulated to contain a total of 180 mcg (60 mcg of each strain) of influenza virus hemagglutinin. (3, 11) CONTRAINDICATIONS Hypersensitivity to egg proteins or life-threatening reactions after previous administration of any influenza vaccine. (4, 11) WARNINGS AND PRECAUTIONS If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of previous influenza vaccination, the decision to give or High-Dose should be based on careful consideration of the potential benefits and risks. (5.1) The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex sensitive individuals. (5.3) ADVERSE REACTIONS Most common ( 10%) injection-site reactions were injection site tenderness, pain, swelling and arm stiffness. (6) Most common ( 10%) systemic adverse events were headache and myalgia. (6) High-Dose Most common ( 10%) injection-site reactions were injection site pain and erythema. (6) Most common ( 10%) systemic adverse events were myalgia, malaise, and headache. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA at (1-800-VACCINE) or VAERS at or USE IN SPECIFIC POPULATIONS Safety and effectiveness of have not been established in pregnant women, nursing mothers, or children <6 months of age. (8.1, 8.3, 8.4) High-Dose Safety and effectiveness of High-Dose have not been established in pregnant women, nursing mothers, or individuals <65 years of age. (8.1, 8.3, 8.4) See 17 PATIENT COUNSELING INFORMATION. Revised: July 2010 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosage and Schedule 2.2 Administration 11 DESCRIPTION 12 CLINICAL PHARMAC OLOGY 12.1 Mechanism of Action 13 NON-CLINICAL T OXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 3 DOSAGE FORMS AND STRENGTHS 14 CLINICAL STUDIES 4 CONTRAINDICATIONS 14.1 Immunogenicity of in Children 5 WARNINGS AND PRECAUTIONS 5.1 Guillain-Barré Syndrome 5.2 Altered Immunocompetence 5.3 Preventing and Managing Allergic Reactions 5.4 Limitations of Vaccine Effectiveness 14.2 Immunogenicity of in Adults 14.3 Immunogenicity of High-Dose in Adults 65 Years of Age and Older 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HAND LING 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Post-Marketing Experience 6.3 Other Adverse Events Associated with Influenza Vaccines 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUN SELING INFORMATION *Sections or subsections omitted from the full prescribing information are not 8 USE IN SPECIFIC POPULATIONS listed. 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use

2 FULL PRESCRIBING INFORMATION: 1. INDICATIONS AND USAGE is an inactivated influenza virus vaccine indicated for active immunization of persons 6 months of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. [See Dosage Forms and Strengths (3).] High-Dose is an inactivated influenza virus vaccine indicated for active immunization of persons 65 years of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. [See Dosage Forms and Strengths (3).] This indication is based on the immune response elicited by High-Dose; there have been no controlled clinical studies demonstrating a decrease in influenza disease after vaccination with High-Dose. 2. DOSAGE AND ADMINISTRATION 2.1. Dosage and Schedule Basic dosing information for and High-Dose, and their respective age indications, are presented in able 1 and Table 2. Page 2 of 24

3 able 1: Vaccination Status and Age Dose/Route Schedule Previously unvaccinated or incompletely vaccinated with an influenza vaccine (ie, no previous dose or vaccinated for the first time in the last influenza season and received only 1 dose) 6 through 35 months 0.25 ml/intramuscular 2 doses at least 1 month apart 36 months through 8 years 0.5 ml/intramuscular 2 doses at least 1 month apart Previously vaccinated with an influenza vaccine (ie, received two doses last influenza season or one or more doses at any time before last season) 6 through 35 months 0.25 ml/intramuscular 1 dose 36 months through 8 years 0.5 ml/intramuscular 1 dose Any vaccination status 9 years and older 0.5 ml/intramuscular 1 dose Table 2: High-Dose Any vaccination status Dose/Route Schedule 65 years and older 0.5 ml/intramuscular 1 dose 2.2. Administration Inspect and High-Dose syringes and vials visually for particulate matter and/or discoloration prior to administration. If either of these conditions exist, the vaccine should not be administered. Shake the syringe or single-dose vial before administering the vaccine and shake the multi-dose vial each time before withdrawing a dose of vaccine. Page 3 of 24

4 Sterile suspension for intramuscular injection is supplied in 5 presentations: 4 presentations of (including 2 dosage strengths in pre-filled syringes) and 1 presentation of High- The vaccine should not be injected into the gluteal region or into areas where there may be a major nerve trunk. For needle length, refer to the Advisory Committee on Immunization Practices (ACIP) recommendations. (1) If or High-Dose are to be given at the same time as another injectable vaccine(s), the vaccine(s) should always be administered at separate injection sites. Pediatrics The preferred sites for intramuscular injections are the anterolateral aspect of the thigh in infants (6-12 months of age) or the deltoid muscle of the upper arm in children (12 months through 17 years of age). Adults 18 years of age and older should be administered as a single intramuscular dose preferably in the deltoid muscle. Adults 65 years of age and older High-Dose should be administered as a single intramuscular dose preferably in the deltoid muscle. 3. DOSAGE FORMS AND STRENGTHS Page 4 of 24

5 Dose in a pre-filled syringe. Dosage strengths of the 3 different pre-filled syringes are distinguished by different colored plungers. Sterile suspension for intramuscular injection supplied in 4 presentations: 1) Prefilled syringe, 0.25 ml, pediatric dose, for 6 through 35 months of age, distinguished by a pink syringe plunger rod. 2) Prefilled syringe, 0.5 ml, for 36 months of age and older, distinguished by a clear syringe plunger rod. 3) Single-dose vial, 0.5 ml, for 36 months of age and older. 4) Multi-dose vial, 5 ml, for 6 months of age and older, contains thimerosal as a preservative. [See Description (11).] Each 0.25 ml dose of contains influenza split virus antigens that are formulated to contain a total of 22.5 mcg of influenza virus hemagglutinin, 7.5 mcg each from the 3 influenza virus strains in the vaccine. Each 0.5 ml dose of contains influenza split virus antigens formulated to contain a total of 45 mcg of influenza virus hemagglutinin, 15 mcg each from the 3 influenza virus strains in the vaccine. [See Description (11).] High-Dose Sterile suspension for intramuscular injection supplied in prefilled syringes, 0.5 ml, for adults 65 years of age and older, distinguished by a gray syringe plunger rod. Page 5 of 24

6 Each 0.5 ml dose of High-Dose contains influenza split virus antigens that are formulated to contain a total of 180 mcg of influenza virus hemagglutinin, 60 mcg each from the 3 influenza virus strains in the vaccine. [See Description (11).] 4. CONTRAINDICATIONS Do not administer or High-Dose to anyone with a known hypersensitivity to egg proteins or any component of the vaccine listed in Table 5 or life-threatening reactions after previous administration of any influenza vaccine. [See Warnings and Precautions (5) and Description (11)]. 5. WARNINGS AND PRECAUTIONS Guillain-Barré Syndrome If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of previous influenza vaccination, the decision to give or High-Dose should be based on careful consideration of the potential benefits and risks Altered Immunocompetence If either or High-Dose are administered to immunocompromised persons, including those receiving immunosuppressive therapy, the immune response may be diminished Preventing and Managing Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. The tip caps of the and High- Page 6 of 24

7 Dose prefilled syringes may contain natural rubber latex which may cause allergic reactions in latex sensitive individuals Limitations of Vaccine Effectiveness Vaccination with either or High-Dose may not protect all recipients. 6. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trial of another vaccine, and may not reflect the rates observed in practice Clinical Trial Experience Pediatric Studies The formulation of was studied in 19 children 6 to 23 months of age and in 12 children 24 to 36 months of age, given in 2 doses one month apart. Local reactions and systemic events were solicited for 3 days after each dose. Most local and systemic reactions were mild. The proportions of local and systemic reactions in children were similar to the proportions in adults. - Adults In two observational studies, 120 adults years of age received a single dose of either the Year or the Year formulations of. Solicited injection site and systemic reactogenicity data were collected for three days following vaccination. The most common (occurring in >10% of the study participants in either of the two studies) solicited events were injection site pain, tenderness, swelling, arm stiffness, headache, and myalgia. Most of the Page 7 of 24

8 solicited injection site and systemic adverse events were reported as mild and resolved within 3 days. High-Dose A total of 3,876 individuals 65 years of age and older were randomized to receive either High-Dose or in a phase 3, multi-center, active-controlled, double-blind trial conducted in the US. The safety analysis set included 2,573 High-Dose recipients and 1,260 recipients. Table 3 summarizes solicited injection site reactions and systemic adverse events collected within 7 days post vaccination via diary cards. Onset was usually within the first 3 days after vaccination and majority of the reactions resolved within 3 days. Page 8 of 24

9 Table 3: Frequency of Solicited Injection Site and Systemic Adverse Events within 7 Days Post-Vaccination High-Dose Percent Percent Injection site reactions Pain Erythema Swelling Systemic adverse events Myalgia Malaise Headache Fever a N is the number of subjects in the Safety Analysis Set. a (N = 2573) (N = 1260) a Solicited injection site reactions and systemic adverse events were more frequent after vaccination with High-Dose compared to standard in adults 65 years of age and older. Table 4 summarizes the severity of solicited adverse events that occurred during the first week after vaccination (2): Page 9 of 24

10 Table 4: Frequency and Severity of Solicited Injection Site and Systemic Adverse Events within 7 Days Post-Vaccination Higha Dose (N = 2573) a (N = 1260) Percent Percent Injection Site Pain Mild Moderate Severe Injection Site Erythema Mild Moderate Severe Injection Site Swelling Mild Moderate Severe Myalgia Mild Moderate Severe Malaise Mild Moderate Severe Headache Mild Moderate Severe Fever Mild Moderate Severe a N is the number of subjects in the Safety Analysis Set Page 10 of 24

11 The rates of Serious Adverse Events (SAEs) were comparable between the two groups; 156/2573 (6.1%) of High-Dose recipients and 93/1260 (7.4%) of recipients experienced SAEs. No deaths were reported within 28 days post-vaccination. A total of 23 deaths were reported during th e follow-up period of the study; 16/2573 (0.6%) among High-Dose recipients and 7/1260 (0.6%) among recipients. The majority of these participants had a medical history of cardiac, hepatic, neoplastic, renal, and/or respiratory diseases Post-Marketing Experience The following events have been reported during the post-approval use of. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including urticaria, angioedema) Nervous System Disorders: Guillain-Barré syndrome ( GBS), convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, paresthesia Vascular Disorders: Vasculitis, vasodilatation/flushing Page 11 of 24

12 Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, pharyngitis, rhinitis Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in extremities, chest pain 6.3. Other Adverse Events Associated with Influenza Vaccines Anaphylaxis has been reported after administration of and other influenza vaccines. Although and High-Dose contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have egg allergy. Allergic reactions include anaphylaxis, angioedema, hives, and asthma. [See Contraindications (4).] The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. If influenza vaccine does pose a risk, it is probably slightly more than 1 additional case/1 million persons vaccinated. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with. It is also not known whether can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Page 12 of 24

13 should be given to a pregnant woman only if clearly needed Nursing Mothers It is not known whether is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when is administered to a nursing woman Pediatric Use Safety and effectiveness of in children below the age of 6 months have not been established. The immune response and safety of was evaluated in 31 children between the ages of 6-36 months. [See Clinical Studies (14).] High-Dose Safety and effectiveness of High-Dose in children have not been established Geriatric Use In two observational studies of in 118 adults years of age and 123 adults greater than 60 years of age, geometric mean antibody titers post vaccination were lower in the older adults [See Clinical Studies (14).]. Page 13 of 24

14 High-Dose High-Dose is indicated for adults 65 years of age and older. [See Indications and Usage (1) and Clinical Studies (14).] 11. DESCRIPTION (Influenza Virus Vaccine) and High-Dose (Influenza Virus Vaccine) are inactivated influenza virus vaccines, for intramuscular use, prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, Octylphenol Ethoxylate (Triton X-100), producing a split virus. The split virus is further purified and then suspended in sodium phosphate-buffered isotonic sodium chloride solution. The High-Dose process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration. and High-Dose are clear and slightly opalescent in color. Antibiotics are not used in the manufacture of or High-Dose. The tip caps of the and High-Dose prefilled syringes may contain natural rubber latex. Vial presentations of do not contain latex. and High-Dose are standardized according to United States Public Health Service (USPHS) requirements and are formulated to contain the amount of HA per 0.5 ml dose Page 14 of 24

15 (see Table 5) for each of the three influenza strains recommended for the Northern Hemisphere influenza season: A/California/07/2009 X-179A (H1N1), A/Victoria/210/2009 X-187 (an A/Perth/16/2009 like virus) (H3N2), and B/Brisbane/60/2008. (1) Table 5: and High-Dose Presentations Quantity (per dose) Component Pediatric (0.25mL Prefilled Syringe) High-Dose (0.5 ml Prefilled Syringe) Active Substance: Split influenza virus, inactivated strains a : 22.5 mcg HA total 45 mcg HA total 180 mcg HA total A (H1N1) 7.5 mcg HA 15 mcg HA 60 mcg HA A (H3N2) 7.5 mcg HA 15 mcg HA 60 mcg HA B 7.5 mcg HA 15 mcg HA 60 mcg HA Other: Sodium phosphate-buffered isotonic QS b to QS b to QS b to appropriate sodium chloride solution appropriate appropriate volume volume volume Formaldehyde 50 mcg 100 mcg 100 mcg Octylphenol Ethoxylate 50 mcg 100 mcg 250 mcg Gelatin 0.05% 0.05% None Preservative Single Dose Presentations None None None Multi-Dose Presentation (Thimerosal) N/A 25 mcg mercury N/A a per United States Public Health Service (USPHS) requirement b Quantity Sufficient 12. CLINICAL PHARMACOLOGY Mechanism of Action Page 15 of 24

16 Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza virus infection. In some human studies, antibody titers 1:40 have been associated with protection from influenza illness in up to 50% of subjects. (3) (4) Antibodies against one influenza virus type or subtype confer limited or no protection against another. Furthermore, antibodies to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for season al epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains (ie, typically two type A and one type B), representing the influenza viruses likely to be circulating in the US in the upcoming winter. Annual vaccination with the current vaccine is recommended b ecause immunity during the year after vaccination declines, and because circulating strains of influenza virus change from year to year. (1) 13. NON-CLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Page 16 of 24

17 and High-Dose have not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility. 14. CLINICAL STUDIES Immunogenicity of in Children In a study of 2 doses one month apart of ( ) in 31 healthy children 6-36 months of age, 77%, 77%, and 48% achieved post vaccination HI titers of 1:40 or greater for the A/H1, A/H3, and B strains, respectively Immunogenicity of in Adults In two observational studies of the immunogenicity of, younger adults (median age: 38, range: 19 through 59 years of age) and older adults (median age: 72, range: 61 through 86 years of age) were evaluated. The following results were obtained after vaccination with a single-dose of either the year (cohort 1999) or (cohort 2000) formulation of. (See Table 6.) Page 17 of 24

18 Table 6: Percentage (%) Achieving an HI Titer 1:40 and 4-Fold Increase in Younger and Older Adults Antigen Titer 1:40 Percent 4-Fold Increase Percent A (H3N2) Cohort 1999 Younger Adults (N = 60) Older Adults (N = 61) Cohort 2000 Younger Adults (N = 58) Older Adults (N = 62) A (H1N1) Cohort 1999 Younger Adults (N = 60) Older Adults (N = 61) Cohort 2000 Younger Adults (N = 58) Older Adults (N = 62) B Cohort 1999 Younger Adults (N = 60) Older Adults (N = 61) Cohort 2000 Younger Adults (N = 58) Older Adults (N = 62) 11 5 N = Number of participants Immunogenicity of High-Dose in Adults 65 Years of Age and Older A total of 3,876 individuals 65 years of age and older were randomized to receive either High-Dose or in a phase 3, multi-center, randomized, active-controlled, double blind trial conducted in the US. Of those, 3,851 (2,576 randomized to High-Dose and 1,275 Page 18 of 24

19 randomized to ) were included in the immunogenicity analysis according to the vaccine they were randomized to receive. (2) Table 7: Demographic Distribution of Participants in the Phase 3 Trial High-Dose (N=2576) (N=1275) Gender (Percent) Age (Years) Female Male Mean ( min, max) 72.9 ( 65, 97) Race (Percent) 75 years and older (%) 35% 72.9 (65, 94) Asian American Indian or Alaska Native Black % Caucasian Hispanic Native Hawaiian or other Pacific Islander Other N = Number of participants in the immunogenicity analysis set The primary endpoint of the study was HI titer 28 days after vaccination. Pre-specified statistical superiority criteria required that (1) the lower limit (LL) of the 2-sided 95% CI of the GMT ratio [ High-Dose/] be greater than 1.50 for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL>0.67), and that (2) the lower limit of the 2-sided 95% CI of the seroconversion rate difference [ High-Dose - ] be greater than 10% for at least two of the strains, and if one strain failed, non-inferiority of that Page 19 of 24

20 strain must be demonstrated (LL>-10%). As shown in Table 8, statistically superior HI titers after vaccination with High-Dose compared to standard dose were demonstrated for two of the three influenza strains. There are no data demonstrating clinically relevant prevention of culture-confirmed influenza or its complications after vaccination with High-Dose compared to standard dose in individuals 65 years of age and older. Page 20 of 24

21 Table 8: GMT Ratios and Seroconversion Rates following Vaccination with High- Dose GMT GMT Ratio Seroconversion % a Difference Met Both Pre-defined Endpoints? c Influenza Strain High-Dose N b =2576 N b =1275 High- Dose over (95% CI) High-Dose N b =2576 N b =1275 High-Dose minus (95% CI) A (H1N1) (1.6; 1.8) A (H3N2) (1.7; 2.0) B (1.2; 1.4) Note: As defined in the study protocol: (22.4; 28.5) (15.1; 21.7) (8.6; 15.0) Yes Yes No a Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination (day 28) titer 1:40 or a 4- fold increase for those with pre-vaccination titer 1:10. b N is the number of subjects in the Immunogenicity Analysis Set. c Predefined superiority endpoint for seroconversion: the lower limit of the two-sided 95% CI of the difference of the seroconversion rates ( High-Dose minus ) is >10%. Predefined superiority endpoint for GMT ratio: the lower limit of the 95% CI for GMT ratio ( High-Dose divided by ) is >1.5. Page 21 of 24

22 15. REFERENCES 1 Centers for Disease Control and Prevention. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2009;58(RR-8): NCT : 3 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103: Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination- ibiting antibody in protection against challenge infection with influenza A2 and B inh viruses. J Hyg Camb 1972;70 : Page 22 of 24

23 16. HOW SUPPLIED/STORAGE AND HANDLING How Supplied The tip caps of the and High-Dose prefilled syringes may contain natural rubber latex. Vial presentations of do not contain latex. Prefil led syringe, without needle, 0.25 ml, package of 10 prefilled syringes per carton (may contain latex) NDC Prefilled syringe, without needle, 0.5 ml, package of 10 prefilled syringes per carton (may contain latex) NDC Single-dose vial, 0.5 ml, package of 10 vials per carton (contains no latex) NDC Multi-dose vial, 5 ml, one vial per carton (contains no latex). The vial contains ten 0.5 ml doses NDC High-Dose Prefilled syringe, without needle, 0.5 ml, package of 10 prefilled syringes per carton (may contain latex) NDC Storage and Handling Page 23 of 24

24 Store all and High-Dose presentations refrigerated at 2 to 8 C (35 to 46 F). DO NOT FREEZE. Discard if vaccine has been frozen. Between uses, return the multi-dose vial to the recommended storage conditions at 2 to 8 C (35 to 46 F). Do not use after the expiration date shown on the label. 17. PATIENT COUNSELING INFORMATION Inform the patient or guardian that and High-Dose contain killed viruses and cannot cause influenza. and High-Dose do not prevent other respiratory infections. Vaccine recipients and guardians should be instructed to report any severe or unusual adverse reactions to their health care provider and/or to VAERS (see Highlights, Adverse Reactions). is a registered trademark of Sanofi Pasteur Inc. Product information as of July Manufactured by: Sanofi Pasteur Inc. Swiftwater PA USA Page 24 of 24